Ischemic Cell Damage

Ischemic cell damage is the injury of a cell arising from reduced blood flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure. The process involves hypoxia from interrupted blood supply, lack of nutrients, and accumulation of toxic metabolites. Damage to the cell can be reversible (function returns when blood flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure resumes) or irreversible (the reversibility threshold has passed). While blood flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure can be restored and allow cell recovery, reperfusion injury is possible in previously ischemic tissues. By producing calcium overload, oxidative stress and inflammatory mechanisms involving immune cells, cytokines, and the complement system, reperfusion can also lead to cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death (often by necrosis). Susceptibility to ischemia is affected by different factors, which include high metabolic activity, the presence of collateral circulation, watershed areas, and the magnitude of ischemia. The organ most susceptible to ischemia is the brain. Other susceptible organs include the heart, kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys, liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver, and the large intestine Large intestine The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Definition

Ischemic cell injury Cell injury The cell undergoes a variety of changes in response to injury, which may or may not lead to cell death. Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Cell Injury and Death is damage arising from a decrease in blood flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure, which leads to hypoxia, lack of nutrients, and accumulation of toxic metabolites.

  • Hypoxia: decreased oxygen supply (blood flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure often maintained)
  • Reperfusion injury: tissue damage from restoration of blood supply after an ischemic event

Cell injury

In cell injury Cell injury The cell undergoes a variety of changes in response to injury, which may or may not lead to cell death. Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Cell Injury and Death, either the cells either cannot adapt or the maximum adaptive response to physiologic or pathologic stimuli is exceeded.

Ischemia and reperfusion injury are 2 causes of stimuli leading to cell injury and death Cell injury and death The cell undergoes a variety of changes in response to injury, which may or may not lead to cell death. Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Cell Injury and Death.

Other injurious stimuli include physical causes such as trauma or radiation, chemicals, loss of critical nutrients, and mutations.

Stages of cell injury and death Cell injury and death The cell undergoes a variety of changes in response to injury, which may or may not lead to cell death. Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Cell Injury and Death:

  • Reversible injury: damage to the cell → ATP depletion → leakage of ions → ion imbalance → cell and organelle swelling
  • Irreversible injury:
    • The reversibility threshold for the cell has passed and cellular function cannot be restored.
    • The cell is committed to cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death.
  • Cell death (via processes such as necrosis and apoptosis)

Cell death

Necrosis (most common cause):

  • Nonphysiological
  • Uncontrolled cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death after irreversible injury
  • Membrane damage causes an influx of calcium → organelle swelling → digestive enzyme release, which leads to:
    • Pyknosis: nuclear shrinkage
    • Karyorrhexis: nuclear fragmentation 
    • Karyolysis: nuclear fading

Apoptosis (small percentage):

  • Programmed cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death
  • Activated by the release of proapoptotic molecules from the mitochondria (physiologic response)
  • Extrinsic pathways: 
    • Fas (CD95) → Fas ligand (FasL)
    • Tumor necrosis factor Tumor necrosis factor Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF) ( TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF))-α → TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF) receptor 1 (TNR1)
  • Intrinsic pathway (mitochondrial pathway):
    • DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure damage → p53 activated → cell cycle Cell cycle The phases of the cell cycle include interphase (G1, S, and G2) and mitosis (prophase, metaphase, anaphase, and telophase). The cell's progression through these phases is punctuated by checkpoints regulated by cyclins, cyclin-dependent kinases, tumor suppressors, and their antagonists. Cell Cycle arrest → p53 activates apoptosis 
    • ↑ Proapoptotic proteins (e.g., BAK and BAX), ↓ antiapoptotic proteins (e.g., Bcl-2) → mitochondria release cytochrome c
    • Cytochrome c binds apoptosis protease-activating factor (APAF)-1 → activation of caspase and endonuclease
  • Perforin/granzyme pathway: 
    • Utilized by cytotoxic T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells and natural killer cells Natural killer cells A specialized subset of T-lymphocytes that exhibit features of innate immunity similar to that of natural killer cells. They are reactive to glycolipids presented in the context of the major histocompatibility complex (MHC) class I-like molecule, CD1D antigen. Lymphocytes
    • Perforin pores are created in target cells, which allow entry of caspase-like granzyme.

Dead cells are replaced by phospholipids and myelin figures, resulting in clarification or phagocytosis by macrophages.

Ischemic Injury

Ischemia

Injury from ischemia can be due to:

  • ↓ Supply of blood: mechanical arterial obstruction (most common):
    • Atherosclerosis Atherosclerosis Atherosclerosis is a common form of arterial disease in which lipid deposition forms a plaque in the blood vessel walls. Atherosclerosis is an incurable disease, for which there are clearly defined risk factors that often can be reduced through a change in lifestyle and behavior of the patient. Atherosclerosis: plaque building up in arterial walls
    • Thromboembolism: blockage of a blood vessel by a clot dislodged from another source in the body
  • ↓ Venous drainage of blood: venous flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure stops:
    • Deep vein thrombosis Deep vein thrombosis Deep vein thrombosis (DVT) usually occurs in the deep veins of the lower extremities. The affected veins include the femoral, popliteal, iliofemoral, and pelvic veins. Proximal DVT is more likely to cause a pulmonary embolism (PE) and is generally considered more serious. Deep Vein Thrombosis: a blood clot in the deep veins Veins Veins are tubular collections of cells, which transport deoxygenated blood and waste from the capillary beds back to the heart. Veins are classified into 3 types: small veins/venules, medium veins, and large veins. Each type contains 3 primary layers: tunica intima, tunica media, and tunica adventitia. Veins
    • Peripheral venous disease: progressive stenosis of veins Veins Veins are tubular collections of cells, which transport deoxygenated blood and waste from the capillary beds back to the heart. Veins are classified into 3 types: small veins/venules, medium veins, and large veins. Each type contains 3 primary layers: tunica intima, tunica media, and tunica adventitia. Veins
  • Shock Shock Shock is a life-threatening condition associated with impaired circulation that results in tissue hypoxia. The different types of shock are based on the underlying cause: distributive (↑ cardiac output (CO), ↓ systemic vascular resistance (SVR)), cardiogenic (↓ CO, ↑ SVR), hypovolemic (↓ CO, ↑ SVR), obstructive (↓ CO), and mixed. Types of Shock:
    • Life-threatening disorder due to lack of blood flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure
    • 4 main types:
      • Hypovolemic: ↓ intravascular volume (e.g., blood loss)
      • Cardiogenic: ↓ left ventricular function (e.g., congestive heart failure Congestive heart failure Congestive heart failure refers to the inability of the heart to supply the body with normal cardiac output to meet metabolic needs. Echocardiography can confirm the diagnosis and give information about the ejection fraction. Congestive Heart Failure)
      • Distributive: septic (from sepsis Sepsis Organ dysfunction resulting from a dysregulated systemic host response to infection separates sepsis from uncomplicated infection. The etiology is mainly bacterial and pneumonia is the most common known source. Patients commonly present with fever, tachycardia, tachypnea, hypotension, and/or altered mentation. Sepsis and Septic Shock), neurogenic (e.g., spinal cord Spinal cord The spinal cord is the major conduction pathway connecting the brain to the body; it is part of the CNS. In cross section, the spinal cord is divided into an H-shaped area of gray matter (consisting of synapsing neuronal cell bodies) and a surrounding area of white matter (consisting of ascending and descending tracts of myelinated axons). Spinal Cord injury), or anaphylactic
      • Obstructive: lack of cardiac outflow (e.g., tension pneumothorax Pneumothorax A pneumothorax is a life-threatening condition in which air collects in the pleural space, causing partial or full collapse of the lung. A pneumothorax can be traumatic or spontaneous. Patients present with a sudden onset of sharp chest pain, dyspnea, and diminished breath sounds on exam. Pneumothorax/tamponade or pulmonary embolism Pulmonary Embolism Pulmonary embolism (PE) is a potentially fatal condition that occurs as a result of intraluminal obstruction of the main pulmonary artery or its branches. The causative factors include thrombi, air, amniotic fluid, and fat. In PE, gas exchange is impaired due to the decreased return of deoxygenated blood to the lungs. Pulmonary Embolism)

Mechanism of injury

  • ↓ Oxygen availability (aerobic metabolism is interrupted) → reduced ATP production → failure of energy-dependent systems:
    • Plasma membrane +Na+-K+ pump (Na⁺, K⁺-ATPase) fails → sodium enters the cell → cell swells
    • Anaerobic metabolism compensates for the ATP loss → depleted glycogen → ↑ lactic acid → ↓ intracellular pH → impaired enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
    • Impaired enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes lead to reduced protein synthesis → detachment of ribosomes 
  • Microscopic changes:
    • Loss of microvilli and formation of “blebs” in the cytoplasm and on the cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane
    • Cell and organelles Organelles A cell is a complex unit that performs several complex functions. An organelle is a specialized subunit within a cell that fulfills a specific role or function. Organelles are enclosed within their own lipid bilayers or are unbound by membranes. The Cell: Organelles swell
  • Cells start to lose functionality.
  • ↑ Intracellular concentrations of water, sodium, and chloride, but potassium
  • All changes are reversible if perfusion and oxygenation are restored. 
  • If ischemia persists, the tissue succumbs to irreversible injury and death.

Reperfusion Injury

Reperfusion

  • Restoration of blood flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure after an ischemic event 
  • Recovery can be achieved (especially with reversible injury).
  • Can paradoxically worsen the injury and lead to cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Deathischemia-reperfusion injury:
    • Reperfusion can exacerbate the damage and injure distant organs when mediators are released into the bloodstream.
    • A clinically significant consideration in the treatment of myocardial infarction Myocardial infarction MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction and stroke

Mechanism of injury

Perfusion is restored, which brings damaging pathways:

  • Oxidative stress: ↑ production of reactive oxygen species (ROS) or free radicals (molecules with an unpaired electron in the outer orbit Orbit The orbit is the cavity of the skull in which the eye and its appendages are situated. The orbit is composed of 7 bones and has a pyramidal shape, with its apex pointed posteromedially. The orbital contents comprise the eye, extraocular muscles, 5 cranial nerves, blood vessels, fat, the lacrimal apparatus, among others. The Orbit and Extraocular Muscles):
    • Produced from leukocytes and damaged cells
    • ↑ Due to mitochondrial damage and the inability to reduce oxygen (impaired antioxidant mechanisms from ischemia)
  • Overload of intracellular calcium:
    • ↑ Calcium → opening of mitochondrial permeability transition pore (mPTP) → ATP depletion
    • ↑ Calcium → cellular enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes (e.g., protease, phospholipase, ATPase, endonuclease) → membrane and nuclear damage
  • Leukocytes and cytokines → recruit more immune cells → ↑ inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation (“sterile inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation”)
  • Complement system activation → complement proteins bind ischemic tissues of antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins → ↑ inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation

The combination of the mechanisms induce:

  • Damage to DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure, structural proteins, and lipids Lipids Lipids are a diverse group of hydrophobic organic molecules, which include fats, oils, sterols, and waxes. Fatty Acids and Lipids
  • Further activation of proinflammatory and prothrombotic cascades

Cellular architecture is lost and cell death Cell death Injurious stimuli trigger the process of cellular adaptation, whereby cells respond to withstand the harmful changes in their environment. Overwhelmed adaptive mechanisms lead to cell injury. Mild stimuli produce reversible injury. If the stimulus is severe or persistent, injury becomes irreversible. Apoptosis is programmed cell death, a mechanism with both physiologic and pathologic effects. Cell Injury and Death follows.

Cellular changes and adaptive responses in ischemic cell damage

Flowchart summarizing the major pathologic events contributing to ischemic (upper panel) and reperfusion (middle panel) components of tissue injury:
In prolonged ischemia, hypoxia leads to depletion of ATP and reduced intracellular pH (from lactate accumulation). ATP-dependent ion transport mechanisms become deranged, causing cellular calcium overload, swelling/rupture, and death.
When oxygen levels are restored (reperfusion), reactive oxygen species (ROS) are generated. Proinflammatory changes also occur: Neutrophils infiltrate ischemic tissues and worsen the ischemic injury. The pathologic events lead to the opening of the mitochondrial permeability transition pore (mPTP) in the inner mitochondrial membrane, which allow passage of molecules into the mitochondria and further impair ATP production.
PFK: phosphofructokinase

Image by Lecturio.

Clinical Relevance

Ischemic damage

  • Infarct: area of necrotic cells in an organ, arising mainly from hypoxia and ischemia:
    • Red or “hemorrhagic” infarct:
      • Affects organs with multiple blood supplies or loose parenchyma allowing blood to leak into tissue (e.g., lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs)
      • From venous infarcts: The vein is blocked, but the artery delivers blood.
      • Reperfusion injury: The restoration of blood flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure causes blood to leak through damaged vessels.
    • Pale/white or “anemic” infarct: injury to organs with a single arterial supply or solid parenchyma (e.g., kidney, heart)
  • Ischemic tolerance time: amount of time to develop irreversible tissue damage after an ischemic injury:
    • Brain:
      • The most susceptible organ to ischemia 
      • The least amount of time before irreversibility occurs
    • Most susceptible organs to reduced blood supply after the brain: The heart/myocardium is the 2nd and the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys are the 3rd.
    • Both skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin and skeletal muscle tolerate longer periods of ischemia:
      • Often seen in the emergency application of tourniquets (sometimes for hours) with little injury to the tissues
      • Release (after the 1st 2 hours) followed by reapplication of compression produces minimal injuries. 
  • Anatomically, some organs have watershed areas (border zone):
    • The regions have dual blood supply, but are located at the most distal reaches of the arteries Arteries Arteries are tubular collections of cells that transport oxygenated blood and nutrients from the heart to the tissues of the body. The blood passes through the arteries in order of decreasing luminal diameter, starting in the largest artery (the aorta) and ending in the small arterioles. Arteries are classified into 3 types: large elastic arteries, medium muscular arteries, and small arteries and arterioles. Arteries.
    • Susceptible to ischemia

Brain

  • With high metabolic activity and low carbohydrate stores, the brain has the highest susceptibility to ischemia.
  • Ischemia occurs when an embolus or thrombus ( ischemic stroke Ischemic Stroke An ischemic stroke (also known as cerebrovascular accident) is an acute neurologic injury that occurs as a result of brain ischemia; this condition may be due to cerebral blood vessel occlusion by thrombosis or embolism, or rarely due to systemic hypoperfusion. Ischemic Stroke) reduces the blood flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure:
    • Survival of tissue depends on:
      • Collateral circulation
      • Duration of ischemia
      • Degree and rapidity of blood flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure interruption
    • Neurons die within 5 minutes in the case of complete blockage.
  • Watershed areas:
    • The border zones of the arterial territories
    • The area between the anterior and middle cerebral artery distribution is at highest risk.
    • Infarcts develop after significant hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension.
Watershed areas indicating brain infarct

Watershed areas and infarcts seen on MRI:
a: Watershed areas between the anterior and middle cerebral arterial territories are seen in the anterior blue shade.
Watershed areas between the middle and posterior arterial territories are seen in the posterior blue shade.
b: Occipital watershed infarct is seen at the boundaries of the middle and the posterior arterial territories.

Image: “Watershed territories” by Clothilde Isabel et al. License: CC BY 4.0

Heart

  • In the setting severe ischemia:
    •  Injury to the myocardium is potentially reversible within 30 minutes.
    • Viability progressively decreases after 30 minutes; irreversibility occurs 6–12 hours later. 
  • The most susceptible tissue in the heart is the subendocardial muscle of the left ventricle.
  • Damage from cardiac ischemia leads to:
    • Stable angina Stable angina Persistent and reproducible chest discomfort usually precipitated by a physical exertion that dissipates upon cessation of such an activity. The symptoms are manifestations of myocardial ischemia. Stable and Unstable Angina: 
      • Angina ( chest pain Chest Pain Chest pain is one of the most common and challenging complaints that may present in an inpatient and outpatient setting. The differential diagnosis of chest pain is large and includes cardiac, gastrointestinal, pulmonary, musculoskeletal, and psychiatric etiologies. Chest Pain) subsides within 15 minutes of rest or with administration of nitroglycerin. 
      • Derived from a mismatch between myocardial oxygen demand and oxygen supply 
    • Acute coronary syndrome:
      • Unstable or crescendo angina: Angina lasting > 20 minutes at rest or with minimal exertion (troponin levels are normal).
      • Non-ST-elevation myocardial infarction Myocardial infarction MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction (NSTEMI): 
        • Myocardial infarction with angina and increased troponin
        • Not associated with elevation of the ST segment on ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG)
      • STEMI: a myocardial infarction Myocardial infarction MI is ischemia and death of an area of myocardial tissue due to insufficient blood flow and oxygenation, usually from thrombus formation on a ruptured atherosclerotic plaque in the epicardial arteries. Clinical presentation is most commonly with chest pain, but women and patients with diabetes may have atypical symptoms. Myocardial Infarction with angina and elevation of the ST segment on ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG)

Kidney

  • Vulnerable due to:
    • A significant amount of cardiac output (25%) moving to the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys
    • Limited collateral blood supply from extrarenal sites
    • High metabolic activity
  • Shows pale/white infarct when ischemic damage occurs
  • Ischemia can occur in cases of:
    • Hypotension
    • Sepsis
    • Surgery 
  • Interruption to complete obstruction of blood supply noted in:
    • Cardioembolic disease (e.g., atrial fibrillation Atrial fibrillation Atrial fibrillation (AF or Afib) is a supraventricular tachyarrhythmia and the most common kind of arrhythmia. It is caused by rapid, uncontrolled atrial contractions and uncoordinated ventricular responses. Atrial Fibrillation)
    • Renal artery injury
    • Hypercoagulable Hypercoagulable Hypercoagulable states (also referred to as thrombophilias) are a group of hematologic diseases defined by an increased risk of clot formation (i.e., thrombosis) due to either an increase in procoagulants, a decrease in anticoagulants, or a decrease in fibrinolysis. Hypercoagulable States state
  • Areas most affected:
    • Proximal tubule (S3 segment): minimal capacity to produce energy in anaerobic conditions
    • The medullary thick ascending limb of the loop of Henle

Liver

  • With a complex vasculature and high metabolic activity, hepatic injury results from severe hypoperfusion.
  • Can occur with an interruption of blood supply to the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver:
    • Hepatic sickle cell crisis 
    • Hepatic artery Hepatic artery A branch of the celiac artery that distributes to the stomach, pancreas, duodenum, liver, gallbladder, and greater omentum. Liver thrombosis
    • Other systemic conditions (e.g., shock, respiratory failure Respiratory failure Respiratory failure is a syndrome that develops when the respiratory system is unable to maintain oxygenation and/or ventilation. Respiratory failure may be acute or chronic and is classified as hypoxemic, hypercapnic, or a combination of the two. Respiratory Failure)
  • Interruption of hepatic blood supply manifests with:
    • Elevation of transaminases 
    • Occasionally with GI symptoms (e.g., nausea, abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain)
  • Often accompanied by other end-organ hypoperfusion (e.g., renal ischemia presenting as ↑ creatinine)
  • Area most affected: zone 3 (area closest to and around the central vein)

Intestine

  • Extensive collateral circulation (protective against hypoperfusion)
  • Even if mesenteric blood flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure decreases by 75% for up to 12 hours, injury is minimal due to collateral circulation.
  • Sources of ischemia:
    • Mesenteric arterial occlusion (thrombosis or emboli)
    • Venous thrombosis (↑ resistance from venous flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure → bowel edema Edema Edema is a condition in which excess serous fluid accumulates in the body cavity or interstitial space of connective tissues. Edema is a symptom observed in several medical conditions. It can be categorized into 2 types, namely, peripheral (in the extremities) and internal (in an organ or body cavity). Edema and ischemia)
    • Nonocclusive mesenteric ischemia Mesenteric Ischemia Mesenteric ischemia is a rare, life-threatening condition caused by inadequate blood flow through the mesenteric vessels, which results in ischemia and necrosis of the intestinal wall. Mesenteric ischemia can be either acute or chronic. Mesenteric Ischemia (splanchnic hypoperfusion)
  • Watershed areas ( large intestine Large intestine The large intestines constitute the last portion of the digestive system. The large intestine consists of the cecum, appendix, colon (with ascending, transverse, descending, and sigmoid segments), rectum, and anal canal. The primary function of the colon is to remove water and compact the stool prior to expulsion from the body via the rectum and anal canal. Colon, Cecum, and Appendix): splenic flexure:
    • Blood supply from the narrow terminal branches of the superior mesenteric artery
    • Griffiths’ point: area of weakness 
  • Rectosigmoid junction:
    • Blood supply from the narrow terminal branches of the inferior mesenteric artery
    • Sudeck’s point: area of weakness

References

  1. El Sabbahy, M., Vaidya, V.S. (2011). Ischemic kidney injury and mechanisms of tissue repair. Wiley interdisciplinary reviews. Systems biology and medicine, 3(5), 606–618. https://doi.org/10.1002/wsbm.133
  2. Friedman, L. (2021). Ischemic hepatitis, hepatic infarction, and ischemic cholangiopathy. UpToDate. Retrieved Aug 20, 2021, from https://www.uptodate.com/contents/ischemic-hepatitis-hepatic-infarction-and-ischemic-cholangiopathy#H2
  3. Kalogeris, T., Baines, C.P., Krenz, M., Korthuis, R.J. (2016). Ischemia/Reperfusion. Comprehensive Physiology, 7(1), 113–170. https://doi.org/10.1002/cphy.c160006
  4. Kalogeris, T., Baines, C.P., Krenz, M., Korthuis, R.J. (2012). Cell biology of ischemia/reperfusion injury. International review of cell and molecular biology. 298 : p.229–317. doi: 10.1016/B978-0-12-394309-5.00006-7 
  5. Kemp, W.L., & Burns, D.K., & Brown, T.G. (Eds.), (2008). Chapter 1. cellular pathology. Pathology: The Big Picture. McGraw Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=499&sectionid=41568284
  6. Lee, J.M., Grabb, M.C., Zipfel, G.J., Choi, D.W. (2000). Brain tissue responses to ischemia. The Journal of clinical investigation, 106(6), 723–731. https://doi.org/10.1172/JCI11003
  7. Mitchell, R., Connolly, A. (2021). The Heart. In Kumar, V., Abbas, A., Aster, J., Robbins, S. (Eds.),Robbins and Cotran Pathologic Basis of Disease (10th ed., pp. 527–555). Elsevier, Inc.
  8. Oakes, S. (2021). Cell injury, cell death and adaptations. In Kumar, V., Abbas, A., Aster, J., Robbins, S. (Eds.),Robbins and Cotran Pathologic Basis of Disease (10th ed., pp. 55–57). Elsevier, Inc.

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